Geographical variations may impact outcomes in chronic obstructive pulmonary disease (COPD). We evaluated differences in baseline characteristics and outcomes between patients enrolled in Latin America compared with the rest of the world (RoW) in the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) trial.
MethodsTIOSPIR®, a 2–3-year, randomized, double-blind trial (n=17116; treated set), compared safety and efficacy of once-daily tiotropium Respimat® 5 and 2.5μg with tiotropium HandiHaler® 18μg. This post-hoc analysis pooled data from all treatment arms to assess mortality, exacerbations, cardiac events, and serious adverse events (SAEs) between both regions.
ResultsAt baseline, patients enrolled in Latin America (n=1000) versus RoW (n=16116) were older, with higher pack-years of smoking history and more exacerbations, but less cardiac history. In this analysis, patients in Latin America versus RoW had an increased risk of death (hazard ratio [HR] [95% confidence interval (CI)]: 1.52 [1.24–1.86]; P<.0001) or moderate-to-severe exacerbation (HR [95% CI]: 1.29 [1.18–1.41]; P<.0001), but a lower risk of severe exacerbation (HR [95% CI]: 0.82 [0.68–0.98]; P=.0333). SAE rates in Latin America were lower versus RoW (incidence rate ratio [IRR] [95% CI]: 0.82 [0.72–0.92]), including cardiac disorders (IRR [95% CI]: 0.68 [0.48–0.97]). Risk of major adverse cardiovascular events were similar (HR [95% CI]: 0.99 [0.71–1.40]; P=.9677).
ConclusionsTIOSPIR® patients in Latin America had a higher risk of death or moderate-to-severe exacerbation, but a lower risk of severe exacerbation than those in RoW. Geographical differences may impact outcomes in COPD trials.
Las variaciones geográficas pueden afectar a los resultados en la enfermedad pulmonar obstructiva crónica (EPOC). Evaluamos las diferencias en las características basales y los resultados de los pacientes incluidos en Latinoamérica en comparación con el resto del mundo (RdM) en el ensayo TIOtropium Safety and Performance In Respimat® (TIOSPIR®).
MétodosTIOSPIR®, es un estudio aleatorizado, doble ciego de 2-3 años de duración (n=17.116; conjunto tratado), comparó la seguridad y la eficacia del tiotropio Respimat® una vez al día en dosis de 5 y 2,5μg con respecto al tiotropio HandiHaler® 18μg. Este análisis post-hoc reunió datos de todos los brazos de tratamiento para evaluar la mortalidad, las exacerbaciones, los acontecimientos cardíacos y los acontecimientos adversos graves (AAG) entre ambas regiones.
ResultadosAl inicio del estudio, los pacientes reclutados en América Latina (n=1.000) versus RdM (n=16.116) eran de mayor edad, con más paquetes/año de consumo de tabaco en sus antecedentes y más exacerbaciones, pero menos antecedentes cardíacos. En este análisis, los pacientes de Latinoamérica versus RdM tenían un mayor riesgo de muerte (razón de riesgo [HR] intervalo de confianza del 95% [IC 95%]: 1,52 [1,24-1,86]; p<0,0001) y de exacerbación moderada a grave (HR [IC 95%]: 1,29 [1,18-1,41]; p<0,0001), pero menor riesgo de exacerbación grave (HR [IC 95%]: 0,82 [0,68-0,98]; p=0,0333). Las tasas de AAG en Latinoamérica fueron más bajas frente al RdM (tasa de incidencia [IRR] [IC 95%]: 0,82 [0,72-0,92]), incluidos los trastornos cardíacos (IRR [IC 95%]: 0,68 [0,48-0,97]). El riesgo de acontecimientos cardiovasculares adversos mayores fue similar (HR [IC 95%]: 0,99 [0,71-1,40]; p=0,9677).
ConclusionesLos pacientes de TIOSPIR® en Latinoamérica tuvieron un mayor riesgo de muerte y de exacerbación moderada a grave, pero un menor riesgo de exacerbación grave que aquellos en el RdM. Las diferencias geográficas pueden afectar los resultados en los ensayos de la EPOC.
Chronic obstructive pulmonary disease (COPD) represents an enormous health burden worldwide. Its prevalence is relatively high in Latin America, affecting an estimated 14.3%1 of the population versus 9.2%2 in the rest of the world (RoW). A substantial proportion of Latin American patients had experienced an exacerbation (18.2%),3 and respiratory causes, including COPD, are amongst the leading cause of mortality in this region.4 Smoking is a behaviour that is seemingly ingrained in Latin American culture,5 with smokers from Latin America constituting 8%–10% of tobacco smokers globally.6 Solid fuels are used by 30%–75% of households7 (traditionally in rural areas8) and contribute to mortality rates similar to those observed in tobacco smokers.9 Management guidelines for COPD recognize that curbing the smoking epidemic10,11 and reducing exposure to pollutants10 are necessary to lower COPD risk in developing countries, but do not detail regional differences in risk, outcomes, or treatment options.
The TIOtropium Safety and Performance In Respimat® (TIOSPIR®) study demonstrated similar efficacy and safety profiles between tiotropium Respimat® (2.5 or 5μg) and tiotropium HandiHaler® 18μg, with respect to risk of mortality and risk of exacerbation.12 A recent TIOSPIR® subanalysis demonstrated similar mortality rates in Asian patients versus RoW. Although exacerbation rates were lower in Asia, a higher proportion of patients had severe exacerbations than in RoW.13
The purpose of this post-hoc analysis was to determine whether there are differences in the baseline characteristics, mortality, exacerbations, cardiac adverse event, and serious adverse event (SAE) outcomes of patients from Latin American geographical region versus RoW in the TIOSPIR® trial.
MethodsStudy designTIOSPIR® (NCT01126437) was a large (N=17135), long-term (2–3-year), randomized, double-blind, parallel-group, double-dummy, event-driven trial in patients with COPD comparing the safety and efficacy of once-daily tiotropium (SPIRIVA® [Boehringer Ingelheim, Ingelheim am Rhein, Germany]) via Respimat® 5μg (2 inhalations of 2.5μg), and 2.5μg (2 inhalations of 1.25μg), or via HandiHaler® 18μg; 17116 patients constituted the as-treated population and were included in this analysis. The study design, detailed methods, and primary results were published previously.12,14
Study populationAll participants had a confirmed diagnosis of COPD (forced expiratory volume in 1 second [FEV1] ≤70% predicted and FEV1/forced vital capacity ≤0.70), were aged ≥40 years, and had ≥10 pack-years of smoking history.14 Patients with concomitant cardiac diseases were included in the study, except those with recent (≤6 months) myocardial infarction (MI), severe arrhythmia, or a change in drug therapy within the previous year; or hospitalization for cardiac failure within the previous year.14 All usual background treatments for COPD, except other inhaled anticholinergics, were allowed.14
The geographical region of Latin America enrolled patients in Argentina, Brazil, Colombia, Guatemala, Mexico, Panama, and Peru.
Outcome measuresOutcomes of interest in this analysis were time to all-cause death, time to first moderate-to-severe or severe exacerbation, time to major adverse cardiovascular events (MACE) and fatal MACE, and SAEs for patients in Latin America versus RoW.
AssessmentsAn independent mortality adjudication committee, blinded to treatment assignments attributed the cause of each death.14 Non-fatal stroke and MI (included in MACE) were reported by study investigators and verified for classification accuracy by central reviewers who were blinded to treatment assignment.
Exacerbations were defined as the worsening of ≥2 major respiratory symptoms (dyspnoea, cough, sputum, chest tightness, or wheezing) for ≥3 days and requiring specified treatment changes. Moderate-to-severe exacerbations required a prescription for antibiotics, systemic corticosteroids, or both (with no hospitalization); severe exacerbations required hospitalization. The onset of exacerbation was defined as the onset of the first recorded symptom; the end of exacerbation was decided by the investigator, based on clinical judgment.
A composite endpoint of MACE was included in the analyses, comprising stroke, transient ischaemic attack (TIA), MI, sudden death, cardiac death, sudden cardiac death, or fatal event in the system organ classes (SOCs) for cardiac and vascular disorders. SOCs were defined according to the Medical Dictionary for Regulatory Activities standardizing attributions of AEs globally.
Statistical analysisBased on similar efficacy and safety results among the tiotropium treatment arms in the primary analysis,12 data were pooled for this post-hoc exploratory analysis.
Baseline characteristics discriminating between patients in Latin America and RoW were identified and compared descriptively.
Hazard ratios (HRs) and 95% confidence intervals (CIs) for time to events by region were calculated using a Cox proportional hazards regression model without covariate adjustment, and displayed via Kaplan–Meier plots. A negative binomial regression model was used to estimate the number of exacerbations. HRs for time to death and time to moderate-to-severe exacerbation analyses, by region and baseline characteristics, are shown as forest plots. Additional analyses of time to death and moderate-to-severe exacerbation, severe exacerbations, and MACE were adjusted for covariates including age, post-bronchodilator FEV1% predicted, gender, exacerbation history, smoking history (pack-years), body mass index (BMI), and history of cardiac disorders, MI, coronary artery disease/ischaemic heart disease (CAD/IHD), cardiac arrhythmia, heart failure (class I–IV), and stroke/TIA.
Incidence rates, incidence rate ratios (IRRs), and 95% CIs for causes of death were calculated. SAEs are provided in the Supplementary Material.
For the mortality analysis (vital status), data were included if death occurred up until the study end date, irrespective of treatment discontinuation. For the exacerbation analysis (on-treatment), events were counted from randomization to drug stop date+1 day, and for MACE to drug stop date+30 days.
ResultsStudy populationOf the TIOSPIR® population, 1000 patients from Latin America and 16116 patients from RoW were included (Table 1). Total exposure to tiotropium was 1855 and 32229 patient-years for Latin America and RoW, respectively. A total of 228 (22.8%) patients from Latin America and 3689 (22.9%) patients from RoW discontinued prematurely from trial medication. Reasons for premature discontinuation were similar, and mainly due to AEs, with respiratory disorders (including COPD) being the most common AEs, followed by neoplasms, and infections and infestations.12 Vital status follow-up was complete for 99.1% and 99.8% of patients from Latin America and RoW, respectively.
Patient baseline characteristics by region.
Characteristic | Latin America (n=1000) | RoW (n=16116) | P-value |
---|---|---|---|
Male, n (%) | 687 (68.7) | 11550 (71.7) | P=.0437 |
Age, n (%) | P<.0001 | ||
<60 years | 225 (22.5) | 4538 (28.2) | |
60–<70 years | 377 (37.7) | 6325 (39.2) | |
≥70 years | 398 (39.8) | 5253 (32.6) | |
BMI, kg/m2, n (%) | P=.0061 | ||
Underweight, BMI<18.5 | 60 (6.0) | 1038 (6.4) | |
Normal, 18.5≤BMI<25 | 434 (43.4) | 6252 (38.8) | |
Pre-obese, 25≤BMI<30 | 321 (32.1) | 5188 (32.2) | |
Obese, BMI≥30 | 185 (18.5) | 3638 (22.6) | |
Duration of COPD, years, mean (SD) | 6.9 (5.4) | 7.5 (6.2) | P=.1064 |
Smoking history, pack-years, mean (SD) | 48.1 (28.6) | 43.5 (24.5) | P<.0001 |
Current smoker, n (%) | 207 (20.7) | 6312 (39.2) | P<.0001 |
Post-BD FEV1, l, mean (SD) | 1.24 (0.46) | 1.35 (0.48) | P<.0001 |
Post-BD FEV1, % of predicted value, mean (SD) | 47.0 (14.3) | 48.4 (13.8) | P=.0021 |
GOLD stage, n (%) | P=.0020 | ||
I+II | 465 (46.5) | 7727 (47.9) | |
III | 397 (39.7) | 6449 (40.0) | |
IV | 130 (13.0) | 1712 (10.6) | |
mMRC scale, n (%) | P=.0471 | ||
0 | 102 (10.2) | 1303 (8.1) | |
1 | 354 (35.4) | 6020 (37.4) | |
>1 | 542 (54.2) | 8773 (54.4) | |
History of cardiac disorder, n (%) | 182 (18.2) | 4287 (26.6) | P<.0001 |
History of MI, n (%) | 38 (3.8) | 988 (6.1) | P=.0026 |
History of CAD/IHD, n (%) | 50 (5.0) | 2544 (15.8) | P<.0001 |
History of cardiac arrhythmia, n (%) | 120 (12.0) | 1705 (10.6) | P=.1597 |
History of heart failure, class I–IV, n (%) | 21 (2.1) | 1317 (8.2) | P<.0001 |
Number of COPD exacerbations treated in last year, n (%) | P<.0001 | ||
0 | 385 (38.5) | 8434 (52.3) | |
1 | 384 (38.4) | 4492 (27.9) | |
>1 | 230 (23.0) | 3179 (19.7) | |
Sputum-producing cough >3mo for 2 years, n (%) | 579 (58.0) | 10307 (64.0) | P=.0001 |
Any pulmonary medication, n (%) | 927 (92.7) | 14573 (90.4) | P=.0170 |
LAMA, n (%) | 242 (24.2) | 7781 (48.3) | P<.0001 |
ICS, LABA, or both, n (%) | P<.0001 | ||
LABA (but not ICS) | 81 (8.1) | 1625 (10.1) | |
ICS (but not LABA) | 126 (12.6) | 1105 (6.9) | |
LABA and ICS | 566 (56.6) | 8306 (51.5) | |
Neither (ICS nor LABA) | 227 (22.7) | 5080 (31.5) | |
Any CV medication, n (%) | 447 (44.7) | 8306 (51.5) | P<.0001 |
Patients with missing baseline characteristics are not shown.
Cardiac history was defined as history of MI, CAD/IHD, cardiac arrhythmia, or heart failure. Any CV medication includes β-blockers, calcium channel blockers, cardiac glycosides (digoxin), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nitrates, anti-arrhythmics class I or III (sodium or potassium channel blockers), adenosine, acetylsalicylic acid, anticoagulants (vitamin K antagonists, direct thrombin inhibitors, and factor Xa inhibitors), and antiplatelets.
BD, bronchodilator; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; FEV1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; IHD, ischaemic heart disease; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; MI, myocardial infarction; mMRC, Modified Medical Research Council; RoW, rest of the world; SD, standard deviation.
At baseline, patients enrolled in Latin America were comparatively older (higher proportion of patients aged ≥70 years), and had higher mean pack-years of smoking history than those in RoW, although a lower percentage were current smokers (Table 1). A higher proportion of patients in Latin America had COPD exacerbation in the year prior to the trial than those in RoW. Latin American patients were more likely to have very severe COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stage IV) versus RoW (Table 1). Fewer Latin American patients had a history of cardiac disorders, or were receiving cardiovascular medication at baseline versus RoW (Table 1). The proportions of patients receiving long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) at baseline were lower in Latin America than in RoW; however, they were more likely to receive inhaled corticosteroids (ICS) (with or without LABA) (Table 1).
MortalityDuring the study, a greater proportion of patients died in the Latin American population (n=100 [10.0%]) versus RoW (n=1200 [7.4%]) (Table 2A). Analysis of time to death confirmed that patients in Latin America had a higher risk of death than those in RoW (HR [95% CI]: 1.52 [1.24–1.86]) (Table 2A; Fig. 1). This was also true when the analysis of time to death was adjusted for age, gender, FEV1% predicted, exacerbation history, smoking history (pack-years), BMI, history of cardiac disorders, MI, CAD/IHD, cardiac arrhythmia, heart failure (class I–IV), and stroke/TIA (HR [95% CI]: 1.37 [1.11–1.69]) (Table 2A).
Latin America (n=1000) | RoW (n=16116) | Latin America vs RoW | |
---|---|---|---|
(A) Deatha | |||
Patients with deaths, n (%) | 100 (10.0) | 1200 (7.4) | – |
Median time to death, days | – | – | – |
HR (95% CI); P-value (without additional covariates) | – | – | 1.52 (1.24–1.86); P<.0001 |
HR (95% CI); P-value (with additional covariates)d | – | – | 1.37 (1.11–1.69); P=.0031 |
(B) Moderate-to-severe exacerbationb | |||
Patients with moderate-to-severe exacerbations, n (%) | 548 (54.8) | 7647 (47.4) | – |
Total number of moderate-to-severe exacerbations, n | 1278 | 17815 | – |
Median time to moderate-to-severe exacerbation, days | 536 |